This project examines a new but poorly understood finding from functional magnetic resonance imaging (fMRI) that is providing new insights into fundamental brain architecture. Functional imaging studies show that similar sets of non-contiguous brain regions are co-activated across a wide range of tasks. Remarkably, many of these co-activations are recapitulated when subjects are at rest. Thus, resting state fMRI (rs-fMRI) is thought to reflect task-related functional networks. It is of great interest to know what principles are responsible for the maintenance of these intrinsic co-activations. Most functional connectivity studies have focused on the cortex. Deep brain structures, including the thalamus, have been implicated in these networks, but little is known regarding exactly what role they might play. Most input to the cerebral cortex passes through the thalamus, including many sensory signals, cerebelar and basal ganglia inputs. As a result, the thalamus is in an ideal anatomical position to regulate or maintain functional connectivity. Focal lesions can reveal much about the structure and maintenance of functional connectivity. Progress in this area has focused on naturally occurring lesions. Experimental lesions in non-human primates can be precisely placed, and repeated to obtain statistical confidence in their effects. Recently, rs-fMRI in non-human primates has revealed cortical networks similar to those observed in humans. Muscimol, a GABAA agonist, can be injected into tissue to inhibit local activity, and the sites of inactivation can be precisely monitored. We propose to use reversible inactivation in the macaque monkey to examine the roles of the thalamus and cortex in maintaining resting state network functional connectivity, and to characterize the effects of inactivation on the networks using novel graph theoretic approaches. This work will shed light on the neuronal underpinnings of cortical connectivity and more generally, may inform rehabilitation approaches for traumatic brain injury and other disorders. PUBLIC HEALTH RELEVANCE: The thalamus and its connections are critical for cognition. Reduced cognitive capacity due to traumatic brain injury is sometimes improved by deep brain stimulation of the thalamus. This work will elucidate the neuronal underpinnings of cortical connectivity underlying normal cognition and may inform rehabilitation approaches for traumatic brain injury.